Selected Properties of Zidovudine

Other names Retrovir, AZT, ZDV

Generic: Apo-Zidovudine (Apotex), Novo-AZT (Novopharm)

Combination formulations:
• Combivir: lamivudine + zidovudine
• Generic: Apo-Lamivudine-Zidovudine
• Trizivir: zidovudine + lamivudine + abacavir
Manufacturer ViiV Healthcare ULC

Pharmacology/Mechanism of • Thymidine analogue, intracellular triphosphorylation to active

Action form with preferential activity in active cells
• Causes viral DNA chain termination via absence of 3'-
hydroxyl group (replaced by azido group) to inhibit HIV
reverse transcription
• Competes with natural nucleoside substrate for binding to
active site of reverse transcriptase
• Inhibits cellular DNA polymerase b and g to a minor extent
Activity In vitro activity in laboratory and clinical isolates of HIV: IC50
and IC90 values of 0.003 to 0.013 and 0.03 to 0.13 mcg/mL,
respectively (1 nM = 0.27 ng/mL). The IC50 and IC90 values of
HIV isolates recovered from 18 untreated AIDS/ARC patients
were in the range of 0.003 to 0.013 mcg/mL and 0.03 to 0.3
mcg/mL, respectively

Resistance - genotypic Mutations in the reverse transcriptase gene associated with

resistance to reverse transcriptase inhibitors (IAS-USA Fall 2005
Resistance Mutations):
• M41L, E44D*, D67N, K70R, V118I*, L210W, T215Y/F,
K219Q/E
*increased level of resistance to stavudine & zidovudine in the
setting of TAMS

• Presence of TAMS confers cross-resistance: M41L, D67N,

K70R, L210W, T215Y/F, K219Q/E
• 69 Insertion Complex is associated with resistance to all
approved NRTIs when present with ≥1 TAM at codons 41,
210 or 215.
• Q151M complex (with A62V, V75I, F77L, F116Y) is
associated with resistance to all approved NRTIs except for
tenofovir.
Resistance - phenotypic Phenotypic data on clinical virus isolates associated with various
TM
mutations using ViroLogic PhenoSense
(http://hivdb.stanford.edu/):
M41L/T215Y: 19-fold ↑ (high resistance)
M41L/210W/T215Y: 64-fold ↑ (high resistance)
D67N +K70R +K219Q: 10-fold ↑ (high resistance)
K70R: 4 fold ↑ (low resistance)
M184V + TAMS: ↑ susceptibility to zidovudine
T215Y: 10-fold ↑ (high resistance)

Academic Copyright. M. Foisy, Pharm.D., Edmonton, AB and A. Tseng, Pharm.D. Toronto, Ontario. Pediatric dosing &
administration information prepared by Natalie Dayneka, Pharm.D., Children’s Hospital of Eastern Ontario, Ottawa. Please note:
This chart summarizes selected properties based on current available data. Please consult a health professional whenever
beginning, stopping or modifying drug therapy. December 2014. www.hivclinic.ca Page 1 of 5
 Cross-Resistance Potential for cross-resistance to other NRTIs depending upon
what mutations develop.
Oral Bioavailability 65%; fatty meal delays rate (3x) and extent of absorption up to
50%
Effect of Food Best on empty stomach. Can take with non-fatty meal to
minimize nausea.
Protein Binding <38 %

Vd 1.6+/- 0.6 L/kg

Tmax 0.5-1.5h (fasting)

Serum T ½ 0.9-1.4h

Intracellular T½ 3-4h

Drug Concentrations AUC 1,400 +/- 200 ng.hr/mL

CSF (% of serum) 60% (4-262%)

2010 CNS Penetration Effectiveness (CPE) Score: 4
[Letendre S et al. 2010]
Metabolism first pass effect; glucuronidation to GZDV (GAZT) and AMT

Excretion • renal excretion of parent (14%) and glucuronide (75%) via

tubular secretion
• renal clearance is 0.34 L/hr/kg parent
• clearance decreases to 18ml/min in uremia
Dosing – Adult po: 600 mg/day in 2-3 divided doses
IV: 1-2mg/kg IV over 1hr q4h (1mg/kg IV q4h = 100mg po q4h)
HIV dementia: 500-1200mg/d po
ITP: 500-900mg/d, dose-related response
Prevention of Vertical Transmission (based on ACTG076
protocol):
• During pregnancy: 14-34 wks pregnancy, 100mg po
5x/day until start of labor (in clinical practice dose is 600
mg/day in 2-3 divided doses to increase compliance; in
addition, at least 2 other antiretrovirals are prescribed).
• Intrapartum (maternal): 2mg/kg (actual body weight) IV
over 1h followed by infusion of 1mg/kg/hr until clamping
of umbilical cord.
• Postpartum (newborn): 2mg/kg po q6h beginning within
12h of birth, until 6 wks, or 1.5mg/kg IV over 30 min q6h;
see Pediatric Dosing for more detailed information
*NB: Note: more current dosing strategies for prevention of
vertical transmission are available (see DHHS Perinatal
Guidelines)
Post-Exposure Prophylaxis: For high risk exposure, 300mg po
bid + 3TC 150mg bid +/- protease inhibitor x 4wks (see current
DHHS guidelines)
Combination tablets
Combivir: 300 mg zidovudine/150 mg lamivudine po BID
Trizivir: zidovudine 300 mg/lamivudine150 mg/abacavir 300
mg po BID
Academic Copyright. M. Foisy, Pharm.D., Edmonton, AB and A. Tseng, Pharm.D. Toronto, Ontario. Pediatric dosing &
administration information prepared by Natalie Dayneka, Pharm.D., Children’s Hospital of Eastern Ontario, Ottawa. Please note:
This chart summarizes selected properties based on current available data. Please consult a health professional whenever
beginning, stopping or modifying drug therapy. December 2014. www.hivclinic.ca Page 2 of 5
 Dosing – Pediatric Neonate/infant (< 6 weeks of age) dose for prevention of
transmission or treatment:
• For prevention of transmission, start ZDV
immediately (preferably within 2 to 6 hours but no
longer than 6 - 12 hours after birth) and administer for
3
6 weeks.
• Less than 30 weeks gestation:
− PO: 2 mg/kg/dose po q12h for 4 weeks, then
increase to 3 mg/kg/dose q12h for last 2 weeks
− IV: 1.5 mg/kg/dose IV q12h for 4 weeks, then
increase to 2.3 mg/kg/dose q12h for last 2 weeks
• ≥ 30 to < 35 weeks gestation:
− PO: 2 mg/kg/dose po q12h for 2 weeks, then
increase to 3 mg/kg/dose q12h for last 4 weeks
− IV: 1.5 mg/kg/dose q12h for 2 weeks, then
increase to 2.3 mg/kg/dose q12h for last 4 weeks
• ≥ 35 weeks gestation:
− PO: 4 mg/kg/dose po q12h
− IV: 3 mg/kg/dose IV q12h
Pediatric treatment dose (6 weeks to < 18 years):
• PO: 240 mg/m2/dose po q12h or:
• MG/KG DOSING: (6 WEEKS OF AGE AND OLDER)
− 4 kg to < 9 kg: 12 mg/kg/dose po BID
− 9 kg to < 30 kg: 9 mg/kg/dose po BID
− ≥ 30 kg: 300 mg po BID
Adult/Adolescent (18 years or older):
300 mg po BID
Special instructions for pediatric Should not be administered with d4T due to poor antiretroviral
patients effect.
May open capsule and give in small portion of food or 5 – 10 mL
cool tap water.
COMBIVIR®: Film-coated immediate release tablet however no
studies, but likely acceptable to crush immediately before
ingestion. May have a bitter aftertaste.
TRIZIVIR®: Film coated immediate release tablet however no
studies regarding stability of split or crushed tablets.
Adjust in Liver Dysfunction 60-400% ↑ AUC observed in patients with moderate-severe liver
disease compared to normal volunteers; reduction in daily dose
may be necessary.
Adjust in Renal Failure/ Dialysis - may require dose reduction or increased dosing interval to
a
CrCl (mL/min) for men: 100-200mg q8-12h in renal dysfunction, but unclear
(140 - age) (wt) x 60 -peritoneal or hemodialysis: 100mg q6-8h po, or 1mg/kg q6-8h
(Scr) (50) IV

Hemodialysis: minimal effect on AZT elimination, enhances

*CrCl (mL/min) for women: GAZT elimination significantly. Administer dose after dialysis
as above multiplied by 0.85 session to avoid potential clinically significant removal of
metabolite.

Academic Copyright. M. Foisy, Pharm.D., Edmonton, AB and A. Tseng, Pharm.D. Toronto, Ontario. Pediatric dosing &
administration information prepared by Natalie Dayneka, Pharm.D., Children’s Hospital of Eastern Ontario, Ottawa. Please note:
This chart summarizes selected properties based on current available data. Please consult a health professional whenever
beginning, stopping or modifying drug therapy. December 2014. www.hivclinic.ca Page 3 of 5
 Toxicity Transient headache and insomnia, malaise (53%), nausea
(50%), anorexia (20%), vomiting (17%), macrocytosis (90%)
unresponsive to B12, anemia: Hgb <80 (1%) may be responsive
to erythropoietin if low baseline endogenous erythropoetin;
neutropenia: ANC< 0.5 (1.8%), myopathy (10%) related to
cumulative dose and ↑ CK, myositis, nail pigmentation (40%).
Rare: thrombocytopenia, hepatotoxicity, cardiomyopathy;
Mitochodrial toxicity: lactic acidosis ± severe hepatomegaly with
steatosis ± pancreatitis, including fatalities. Some patients
develop ventilator-dependent respiratory failure. D/C all
antiretrovirals; partial or complete recovery may take months.
Pregnancy & Lactation Pregnancy risk category C. ~ 85% placental transfer. No
evidence of human teratogenicity. No fetal malformations in
animal studies, but embryotoxic to mouse embryo.Well-
tolerated, short-term safety demonstrated for mother and infant.
Use regular adult dosing during pregnancy. Preferred NRTI as
part of HAART regimen in pregnancy. Avoid use if toxicity found
or d4T is used.
Unknown whether AZT excreted into human breast milk,
however it is secreted into the milk of lactating mice; avoid
breast-feeding to avoid postnatal HIV transmission
Glaxo-Wellcome registry to follow prenatal exposure to
antiretrovirals:1-800-387-7374
Drug Interactions Potential for additive/synergistic toxicity when co-administered
with:
bone marrow toxins: Septra, ampho B, dapsone, flucytosine,
pentamidine (CBC weekly, may hold AZT during acute PCP tx
with Septra);
- neutropenia with ganciclovir (hold AZT during induction,
restart with caution); sulfadiazine/ pyrimethamine can ↑
anemia, ↓ AZT clearance, AZT may ↓ pyrimethamine effect vs
toxo (may hold AZT during toxo tx, or switch antiviral)
D4T inhibits AZT intracellular phosphorylation in vitro, both
thymidine analogues thus avoid combination
Probenecid ↑ AZT 80%, monitor closely or avoid combo
See separate drug interaction chart.
Baseline Assessment CBC/diff (incl MCV), CK, electrolytes, anion gap, serum
bicarbonate, LFTs
Routine Labs CBC/diff q 3 months, CK/LFTs, electrolytes, anion gap, serum
bicarbonate q3-6mos
Measure serum lactate if low serum bicarbonate or high anion
gap and Sx of lactic acidosis. Prodromal Sx include: nausea,
anorexia, abdominal pain, vomiting, weight loss, fatigue. Rapidly
progressive Sx: tachycardia, tachypnea, hyperventilation,
dyspnea, muscular weakness, jaundice, mental status changes.
May also progress to multi-organ failure (hepatic, pancreatitis,
encephalopathy, respiratory) and death.
D/C drug: Sx of lactic acidosis, serum lactate > 5 mmol/L; sx of
myopathy (4-8wk to resolve), Hgb <80 or persistent sx, ANC <
0.5, LFTs ↑ >4-5x ULN

Academic Copyright. M. Foisy, Pharm.D., Edmonton, AB and A. Tseng, Pharm.D. Toronto, Ontario. Pediatric dosing &
administration information prepared by Natalie Dayneka, Pharm.D., Children’s Hospital of Eastern Ontario, Ottawa. Please note:
This chart summarizes selected properties based on current available data. Please consult a health professional whenever
beginning, stopping or modifying drug therapy. December 2014. www.hivclinic.ca Page 4 of 5
 Dosage Forms Retrovir®:
• Capsule: 100mg (white & blue); DIN 01902660
• Syrup: 50mg/5mL (240mL bottle), strawberry flavour; DIN
01902652
• IV: 200mg/20mL vial

Combination tablets
• Combivir: 300 mg zidovudine/150 mg lamivudine tablet;
DIN 02239213
• Apo-Lamivudine-Zidovudine®: 150/300 mg tablet, DIN
02375540
• Trizivir: zidovudine 300 mg/lamivudine150 mg/abacavir
300 mg tablet; DIN 02244757.

Generic:
• Apo-Zidovudine® (Apotex) 100 mg capsule; DIN 01946323
• Novo-AZT® (Novopharm) 100 mg capsule; DIN 01953877

Storage Store all dosage forms at room temperature.

References:
ViiV Healthcare ULC. Retrovir Product monograph. Montreal, QC, February 16th, 2010.

Letendre S, Ellis RJ, Deutsch R, Clifford DB, Collier AC, Gelman GG, et al. Correlates of time-to-loss-of-
viral-response in CSF and plasma in the CHARTER Cohort: CPE score predicts CSF suppression
th
[abstract 430]. 17 Conference on Retroviruses and Opportunistic Infections, San Francisco, CA,
February 16-19, 2010.

Academic Copyright. M. Foisy, Pharm.D., Edmonton, AB and A. Tseng, Pharm.D. Toronto, Ontario. Pediatric dosing &
administration information prepared by Natalie Dayneka, Pharm.D., Children’s Hospital of Eastern Ontario, Ottawa. Please note:
This chart summarizes selected properties based on current available data. Please consult a health professional whenever
beginning, stopping or modifying drug therapy. December 2014. www.hivclinic.ca Page 5 of 5